Perphenazine-Macrocycle Conjugates Rapidly Sequester the Aβ42 Monomer and Prevent Formation of Toxic Oligomers and Amyloid.

"The authors declare no competing financial interest."

"The work was funded by Australian Research Council Discovery Project grant (DP200102463) to M.S., A.K., and P.J.R. S.R.B., J.S.P.A., and M.A.S. were supported by Research Training Program Scholarships from the Australian Government (Department of Education, Skills and Employment). M.K., M.A.S., and E.L.W.’s research is supported by the National Health and Medical Research Council of Australia (NHMRC; APP1132524). M.K. is an NHMRC Principal Research Fellow (APP1154692). M.R.Z. acknowledges support from the Herchel Smith Fund. The authors thank Elva (Meng) Shi and Dr. Malcolm Spain for assistance with synthesis and characterization of compounds and Dr. Bill Bubb for comments on the manuscript. The authors acknowledge the facilities and the scientific and technical assistance of staff within the Sydney Analytical and Sydney Microscopy & Microanalysis Core Research Facilities at the University of Sydney. The authors acknowledge and pay respect to the Gadi people of the Eora Nation, the traditional owners of the land on which we research, teach, and collaborate at the University of Sydney. Supporting Information Available: The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.2c00498.Supplementary methods detailing synthesis of perphenazine conjugates, characterization by nuclear magnetic resonance spectroscopy and screening using synthetic Aβ42, concentration dependences, concentration-dependent inhibition, effect of perphenazine and EGCG, and fitting results (Figures S1–S16), statistical results for the one-way ANOVAs presented in Figure 3 (Tables S5–S9), rate constants and mean squared errors from presented fits of ThT fluorescence data and effective monomer concentrations used for Figure 5 (Tables S8–S12), and SI references (PDF)"